Edited by: Sharon Glynn Lynch, University of Kansas Medical Center, United States
Reviewed by: Andreia Barroso, Brigham and Women’s Hospital and Harvard Medical School, United States; Ulises Gomez-Pinedo, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Spain
*Correspondence: Georgios Papazisis,
This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Increased prevalence of depression has been observed among patients with multiple sclerosis (MS) and correlated with the elevated levels of proinflammatory cytokines and the overall deregulation of monoaminergic neurotransmitters that these patients exhibit. Antidepressants have proved effective not only in treating depression comorbid to MS, but also in alleviating numerous MS symptoms and even minimizing stress-related relapses. Therefore, these agents could prospectively prove beneficial as a complementary MS therapy.
This review aims at illustrating the underlying mechanisms involved in the beneficial clinical effects of antidepressants observed in MS patients.
Through a literature search we screened and comparatively assessed papers on the effects of antidepressant use both
Antidepressants were efficient in tackling numerous aspects of disease pathophysiology both
Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS), involving inflammatory, neurodegenerative and autoimmune patterns in its pathogenesis (
A significant factor that has been repeatedly held responsible for igniting MS relapses are stressful life events (SLEs) (
Serotoninergic routes are highly responsible for modulating both our autonomic and neuroendocrine reactions to stressful stimuli, as serotonin constitutes a major HPA axis modulator (
With respects to serotonin or 5-hydroxytriptamine (5-HT), it displays immunomodulatory properties, interfering with T-cell activation, cytokine release from monocytes, and natural killer (NK) cell stimulation (
In parallel, solid evidence provided by clinical trials has demonstrated that the use of the SSRI escitalopram in women with MS was effective in preventing stress-related relapses (
Accumulating evidence suggests that several motor and non-motor symptoms of MS can be attributed to pathologically reduced levels of key neurotransmitters (
It is worth noting that these key neurotransmitters display both neuronal and immunomodulatory properties, as 5-HT, NE and GABA not only regulate immune cell function (
As already mentioned, MS is a chronic, autoimmune and demyelinating disease of CNS. While MS is only found in humans, many
According to a review on MS animal models, the experimental autoimmune encephalomyelitis (EAE) model is one of the most representative
The MS induction on
Toxin-induced demyelination models are based either on linear inoculation of gliotoxins in the white matter, including ethidium bromide (EtBr) and lysolecithin, or on systemically administered toxins, with cuprizone being the most representative. These models offer duplicability, while the demyelinated area is distinct for further remyelinating studies. Furthermore, ethidium bromide, a toxic intercalating agent, affects both the nucleus DNA and the mitochondrial DNA, but offers well established predictable results, as the magnitude of demyelination is concentration-dependent. Lyso-phosphatidylcholine (lysolecithin) has been used for almost 50 years. Its mechanism of action in the demyelinating process is based on its physicochemical properties, as it can act as a detergent-like agent with selectivity over the myelin-producing cells marking and engaging T and B cells, like activated macrophages. This method can also be implemented in non-human primates, while also the demyelination can be performed in a spatiotemporal manner. On the contrary, this method does not lead to any immune response resembling the one recognized during multiple sclerosis (
Certain other toxins possess analogous demyelinating toxic results but are not in general use. Examples include ionomycin, a calcium ionophore, 6-aminonicotinamide, an antimetabolite of niacin and diphtheria toxin. Antibody-mediated demyelination is also an acknowledged animal model of induced demyelination by galactocerebroside antibodies. Finally, this class of methods included cuprizone, a copper-chelating agent, which has been shown to be toxic for myelin, affecting both white and grey matter leading to oligodendrocyte apoptosis, mitochondrial enzyme malfunction and activation of microglia. Like lysolecithin, cuprizone can also be performed in a spatiotemporal manner while interest is focused on the combined use of cuprizone with other methods of demyelination induction like EAE.
There is growing indication that certain viruses are involved in the pathogenesis of MS, functioning like environmental triggers. The Epstein-Barr virus (EBV) is a typical example that has long been associated with autoimmune conditions including multiple sclerosis despite the exact cause still remains unknown (
The most established
Active EAE requires mice, rats, guinea pigs or nonhuman primates, the use of a myelin-related antigen and concomitant injections of pertussis toxin, leading to activated myelin-specific T cells and encephalitogenic lymphocyte–mediated demyelination. Conversely passive EAE is based on the administration of activated, myelin– specific T cells. Passive EAE evolves faster, does not require any adjuvant and showcases better homogeneity, however its main limitation is that the myelin antigen–specific T cells might not have the desired encephalitogenic capacity, when used
EAE is also affected by the animal strains or species used. The leading option for animals that can accurately imitate the pathophysiology of MS are mice and rats of different strains including Lewis, Dark Agouti (DA) and Brown Norway (BN). Additionally, non-human primates including common marmosets (Callithrix jacchus) and rhesus monkeys (Macaca mulatta), can also be used for
Therefore, the aim of this review is to provide readers with a useful insight into pre-clinical findings regarding the immunomodulatory effects of antidepressants in
We systematically searched the literature for studies investigating the effects of antidepressants on
The following keywords were used: for
The inclusion criteria for
Articles were excluded if: i) the study did not evaluated MS, ii) the pharmacological agent had antidepressant properties but no clinical use as an antidepressant iv) only the abstract was available, v) the research involved patients. In total, our search yielded 271 articles of which 6 were eligible as abstracts. Finally, after the full text of each article was retrieved and all our inclusion criteria were met, 4 articles were included (
Flow chart of
Inclusion criteria for
Articles were excluded if i) the study did not evaluated MS, ii) no behavioral tests were used, iii) the pharmacological agent had antidepressant properties but no clinical use as an antidepressant iv) only the abstract was available, v) the article was a review or a case report. In total, our search yielded 59 articles of which 27 were eligible as abstracts. Finally, after the full text of each article was retrieved and all our inclusion criteria were met, 16 articles were included (
In our research we ended up with 4 studies on antidepressants use, on
Ghareghani et al. used murine embryonic neural stem cells from Lewis rat embryos to study the effects of fluvoxamine performing MTT assay to assess cell viability, Real-time PCR, Western blot analysis and Immunofluorescence (IF) analyses. Fluvoxamine was found to act through the Notch signaling pathway, enhancing cell proliferation transcription factors at even low concentrations. Astrocyte, oligodendrocyte and neuron differentiation was observed to be upregulated which may be attributed to upregulation of the mRNA expression of Notch1, Hes1 and Ki-67 (
In their study Faissner et al. used cell cultures from both human (brain tissues and peripheral blood mononuclear cells) and murine (splenocytes) origin. Neurotoxicity was induced by rotenone, while HORAC assay, Flow cytometry, live cell imaging, Immunocytochemistry and microscopy were performed. The researchers concluded that Clomipramine, Desipramine, Trimipramine, Imipramine and Doxepin all belonging to the tricyclic antidepressant class, exert beneficial effects in the treatment of MS. Prevention of neuronal loss and antioxidative effects were also observed, while T-cell and activated B-cell proliferation, TNF-a production and plasma membrane compromise were all reduced. These findings highlight an overall neuroprotective activity, that is of pivotal importance for a demyelinating autoimmune disease like MS (
The
Dose-dependent relief of mechanical allodynia in the bilateral hind paws of EAE mice was also observed after treatment with amitriptyline, a tricyclic antidepressant. In addition, pharmacological intervention with chronic application of amitriptyline in the mild MOG-EAE mice model resulted in a decreased startle reaction and increased hippocampal norepinephrine levels. Another group of researchers (
In another study, researchers used splenocytes, encephalitogenic T cell clones, primary peritoneal macrophages and brain and spinal cord sections from female mice after the EAE protocol was performed
According to Taler et al, antidepressants, especially SSRIs, display an immunomodulatory activity by reducing immune cell viability and attenuating of pro-inflammatory cytokine secretion. In particular, their research demonstrated that treatment of EAE mice with sertraline alleviated the neurological symptoms of MOG-induced chronic EAE (
Furthermore, treatment of EAE mice with the SNRI venlafaxine ameliorated EAE symptoms in a dose-dependent manner. Venlafaxine exerted its beneficial effects through suppression or enhancement of mRNA expression of proinflammatory and anti-inflammatory factors, respectively. These proinflammatory factors include IFN-γ, TNF-a, IL-12, chemokine CCL-2, CCL-5. On the contrary, venlafaxine increased mRNA expression of the neurotrophic factor BDNF.
Moreover, phenelzine a MAO inhibitor, has been used as a treatment in established EAE- female C57/BL6 mice. It was observed that phenelzine delayed the onset of clinical signs, reduced impairments, ameliorated locomotor function and demonstrated antinociceptive effects. The aforementioned benefits derive from phenelzine’s ability to normalize the levels of GABA and biogenic amines that have been shown to possess anti-inflammatory properties. In particular, phenelzine increased the levels of 5-HT, NE, DA within the spinal cord, brain and brainstem. Lastly, phenelzine normalized pre-synaptic excitatory synaptic densities in S1 and neuronal morphologies.
(
Comparative assessment of
Ref | Drug | Drug Con. | Cell culture/Slice | Methods | Intracellular signaling/Transcriptional | Results | Comments |
---|---|---|---|---|---|---|---|
factors | |||||||
|
|
0,1- 1-5-50-100 -500 nM |
|
MTT assay |
|
- ↑ cell viability(0,1-1-5nM) | Flu acts through Notch signaling pathway to enhance cell proliferation |
Real-time PCR | -↑self-renewal capacity of NSCs (neurosphere formation) (1,5, 50nM) | ||||||
Western blot | -Toxic con (500nM) ↑eNSCs differentiation (1 and 5 nM) | ||||||
Neurosphere assay | ↑astrocytes and neuron differentiation (5nM) | ||||||
↑oligodendrocyte differentiation (1nM) | |||||||
|
Immunohistochemistry, ELISA | ↑IL-4, ↓IFN-γ | |||||
↓IFN-γ/IL-4 ratio (Th1 indicator) | |||||||
0,1- 1-5 nM |
|
Neuropathological analysis 17 dpi, quantitative analysis | ↓ infiltration of lymphocytes into CNS white matter, ↓inflammatory infiltration with extensive perivascular cuffing, ↓number of infiltrated cells/field | ||||
GFAP staining, Western blot, HPLC | ↓surface areas of demyelination plaques | -Fluvoxamine ameliorates the severity of EAE by inhibiting IFN-γ release and promoting IL-4 production from Th1 and Th2 cells, respectively | |||||
↑MBP in demyelination areas | Fluvoxamine reduces demyelination areas by 0,81% | ||||||
GFAP positive staining | Serum lactate is an EAE and MS progression biomarker | ||||||
↓serum lactate levels | |||||||
|
|
10 μM |
|
FeSO4 - - mediated neurotoxicity |
|
-Complete prevention of neuronal loss | |
Anti-MAP-2 Ab staining |
|
-protective activity | |||||
Ronetone-induced neurotoxicity | -antioxidative effect even stronger than gallic acid | ||||||
HORAC assay | ↓proliferation of T-cells | ||||||
5 μM |
|
B-cell isolation | ↓activated B-cell proliferation | ||||
FeSO4 - - mediated neurotoxicity | ↓TNF-a production | ||||||
2 μM |
|
Anti-MAP-2 Ab staining | -strong protection | ||||
Live-cell imaging | -significant ↓ of plasma membrane compromise (destruction) | ||||||
|
|
Ronetone-induced neurotoxicity |
|
↓proliferation of T-cells | |||
|
↓neurotoxicity | ||||||
|
↓proliferation of T-cells | ||||||
|
|
↓proliferation of T-cells | |||||
|
↓transcripts encoding IFN-γ, TNF-a, IL-12, Ccl2 | ||||||
|
Immunohistochemistry PCR | ||||||
LC-MS assay | |||||||
Iba1 staining | |||||||
|
|
↓parenchymal inflammation with only a few cells in the meninges | |||||
|
↓microglial activation and infiltration | ||||||
↓axonal damage | |||||||
|
25 mg/kg |
|
Clomipramine serum levels were 751 nM, whereas 28 μM in spinal cord | -High brain to plasma ratio of Clomipramine | |||
|
|
10-4 to 10-8 mol/l |
|
Determination of cytokines in culture supernatants by ELISA | ↓secretion of TNF-a and IFN-γ | -The effect was more pronounced for IFN-γ and IL-12 p40 with an overall reduction of secretion by 50% | |
|
↓secretion of TNF-a, IFN-γ, IL-6, Ccl5, IL-12 p40, ↓secretion of TNF-a and IL-6 | -Venlafaxine reduced expression levels of Ccl5, IL-6 and TNF-a dose-dependently | |||||
↓CNS inflammation | -Toxicity observed when concentration of Venlafaxine exceeded 10-3mol/l | ||||||
|
Immunohistochemistry – | No reactive gliosis, ↓GFAP gene expression, ↓T cell gene expression (CD3, CD8) in inflamed spinal cord tissue, ↓Granzyme B gene expression in NK cells (in high doses of Venlafaxine) | Venlafaxine reduces the histopathological manifestation of EAE | ||||
GFAP immunostaining | Highest suppressive effect at 60 mg/kg/d | ||||||
6-20-60 mg/kg |
|
↓IL-12 p40, TNF-a, IFN-γ, ↓transcripts of chemokines Ccl2 and Ccl5, ↑mRNA expression of BDNF (for high doses of Venlafaxine) | Venlafaxine reduces the mRNA expression of inflammation-related genes in spinal cord tissue of EAE mice at day 48 after disease induction | ||||
|
|
20 μM, 40 μM |
|
Lysosomal hydrolase assay | Displacement of ASMase from the late endosomic/lysosomic membrane | -Inhibition of ASMase | Desipramine reduced ASMase without significant inhibition of other lysosomal hydrolases |
RT-PCR | -No inhibition of β-D-glucosidase | ||||||
|
Western blot (with anti-ASMase polyclonal Ab) |
Results of
Comparative assessment of
Study | Type of antidepressant (SSRI, SNRI, MAO inhibitors) | Dose | Induction of EAE Protocol | Signs of EAE | Preventive or symptomatic treatment | Study Design | (Species) Age/gender/Weight | Methods | Clinical results | Biological results |
---|---|---|---|---|---|---|---|---|---|---|
(drug administration) | ||||||||||
|
|
5mg/kg | Immunization (SC) with Mog/peptide encompassing amino acids 35-55 of rat | Onset 14/15 dpi and increasing severity 18-25 dpi | 7 days after EAE induction | 5 groups (10 mice each) | 8 weeks old C57/BL female mice Approximately 20g body weight (BW) | Cell viability assay Thymidine incorporation ELISA | Sertraline attenuates neurological symptoms and clinical progression of disease Paroxetine does not affect the clinical score of EAE | ↓ |
|
and 3 times weekly for 3 weeks (IP) | I) healthy mice saline treated-controls | sertraline may serve as an add-on option especially in co-morbid major depression | ↓pro-inflammatory cytokines (INF-γ, TNF-a, IL-2) from |
||||||
(Paroxetine) | II) EAE mice saline treated | |||||||||
III) EAE mice treated sertraline(5mg/kg) | ||||||||||
IV) EAE treated dexamethasone (1mg/kg) | ||||||||||
V) EAE treated paroxetine(5mg/kg) | ||||||||||
|
|
20mg/kg | Immunization (SC) with peptide proteolipid protein PLP 139-151 {100mg PLP 139-151 in emulsion 1:1 with CFA containing 4mg/ml M. Tuberculosis H37Ra | Onset 10 dpi and peaked 13dpi | Once daily/orally | 10 per treatment group | 8-10 weeks old Female wild type SJL/J mice ( |
ELISA kit Flow cytometry Cell proliferation assay | Decline in mean clinical scores in both groups Fluoxetine delayed onset of EAE and reduced peak illness severity (13-15 days) Ameliorated established EAE | ↓immune response (both |
|
I) at the time of immunization | at the time of immunization | ↓ cytokines (TNF-a, INF-γ, IL-6, IL-10) | |||||||
(delayed-onset model) | I) vehicle group | ↓inflammation by directly acting on APC and naive T-cells | ||||||||
II) at the time of peak disease (day 13) | II) fluoxetine group | ↑activation-induced cell death (AICD) (FAS-ligand mediated mechanism) | ||||||||
(amelioration model) | At the time of peak disease (day 13) | ↑CD4-T-cell apoptosis | ||||||||
I) vehicle group | ||||||||||
II) fluoxetine group | ||||||||||
|
|
10mg/kg | (IP) 200μg of guinea pig spinal cord | Onset of clinical symptoms (piloerection) approximately 4-5 dpi Peak 16 dpi (acute EAE) | Once daily (Fx or saline) | 4 groups, | 6-8weeks old | ELISA kit | ↓ of EAE clinical symptoms (Fx 10/Fx 20) | ↓proinflammatory cytokine INF-γ in serum (Fx10 on day 16) |
|
20mg/kg | for 14 days prior to immunization | 15 per group | Female Wistar rats | Histological analysis | Elimination of inflammatory foci and demyelination in the spinal cord (Fx10) | No difference in serum concentration of TNF-a | |||
|
-Control | 160-180 g body weight (BW) | High mortality at dose 20mg/kg | |||||||
-Saline /control | ||||||||||
(200μl saline intragastric)/ | ||||||||||
-10mg/kg fluoxetine (Fx10) | ||||||||||
-20mg/kg fluoxetine (Fx20) | ||||||||||
|
|
30 mg/kg | EAE induced | Onset of clinical signs 9dpi | Once daily (i.p) after the 14 day post EAE induction | 6 groups | 5 weeks old female Lewis rats | Actimetry scores | Duloxetine prevented cold allodynia and showed anti-nociceptive effect on cold hyperalgesia (21 to 28 dpi) | |
|
-solely by MBP | 10 per group | 150-175 g body weight (BW) | Rotarod (locomotor activity) | Duloxetine relieved cold hyperalgesia on tail region | |||||
- MBP plus Cyclosporine A (injected subcutaneously three times /week for | -saline | Von Frey test (allodynia/hyperalgesia | Duloxetine does not prevent mechanical hyperalgesia | |||||||
21 days | -EAE + cyclo | Paint-brush test (mechanical allodynia) | ||||||||
(1ml CFA/ 4 mg Mycobacterium butyricum/ 500 lg of MBP in | -EAE + cyclo + Acetaminophen | Pinch test (hyperalgesia) | ||||||||
0.1 ml of saline) | -EAE + cyclo + Gabapentin | Measure of thermal (cold/heat) allodynia/hyperalgesia | ||||||||
-EAE + cyclo + Tramadol | ||||||||||
-EAE + cyclo + Duloxetine | ||||||||||
|
|
50mg/kg | (SC) 200μl of a 1:1(V/V) mixture of 1g of Guinea Pig Spinal Cord (GPSC) in 1 ml PBS and complete Freud’s adjuvant (CFA) and 1mg/ml enriched M. tuberculosis bacteria | Onset of clinical signs day 12 | Treatment initiated (IP) from clinical onset (d 12) for 6 consecutive days(12-17d) | 3 groups. | 8-12 week old | Immunofluorescent analysis | ↓ clinical scores | ↓pro-inflammatory cytokine INF-γ in serum |
|
(after immunization) | 7 per group | Adult Lewis rats 150-175g body weight (BW) | Western blotting | ↓immune cell infiltration into CNS | ↑anti-inflammatory IL-4 | ||||
- Control (PBS) | HPLC | ↓Plaque demyelination (spinal cords) | ↑Myelin Basic Protein (MBP) | |||||||
-Vehicle (PBS)+ EAE | Histopathological analysis (H/E, LFB) | EAE amelioration | ↑glial fibrillary acid protein (GFAP) | |||||||
-Fluvoxamine +EAE | Immunohistochemical staining | ↓lactate serum levels (MS biomarker) | ||||||||
|
|
10mg/kg | (Suboptimal immunization protocol-mild EAE) | Mild motor deficits (tail weakness) 60d.p.i | 20 days after immunization | 4 groups | 10-12 weeks old female C57BL/6 mice | Rotarod |
|
|
|
Immunization (SC) with 50μg MOG 35-55 | (Mild EAE protocol) | Once daily (IP) | I)control/saline (n=5) | Open field | ↓exploratory behavior | ↓NE and 5-HT | |||
After 20 days of treatment behavioral analyses were performed | Light/dark box | ↑startle reaction | ↑TNF-a | |||||||
II) control/saline +amitriptyline (n=5) | Startle response | ↑LH behavior(depressive-like) | Histopathological alterations in hippocampus | |||||||
III) MOG + saline (n=11) | Learned helplessness (LH) | ↓neuronal cells |
|
|||||||
IV)MOG + amitriptyline (n=10) | Stereological quantification |
|
↑norepinephrine level in the hippocampus | |||||||
Immunohistochemistry | ↓startle response | |||||||||
Real-time PCR | ↓ anxiety-like and depressive-like behavior | |||||||||
HPLC | ↓motor impairment | |||||||||
|
|
3mg/kg | Immunization (SC) with 100 μl of an emulsion containing 200μg of or 100 M. Tuberculosis H37Ra and 50μg of PLP139-151 or PLP178-191in CFA | Onset of remission approximately 15-20 dpi | 20 days after immunization | 5 groups,10 per group | 6-7 weeks old female SJL/J mice | ELISA | High dose of Nortriptyline moderates disease severity |
|
|
5mg/kg | (induction of R-EAE) | Treatment for 21 days via oral gavage | I) vehicle-control | Reversed phase HPLC/MS/MS |
|
[des(3mg/kg) + nor (10mg/kg)] | |||
10mg/kg | II) desloratadin (3mg/kg) | Delayed type hypersensitivity (DHT) assay |
|
↓infiltration to the CNS of CD4+ T cells | ||||||
III) nortriptyline (3mg/kg) | Flow cytometry | Decrease EAE in SJL/J mice | Alters peripheral T-cell response and cytokine production | |||||||
IV) desloratadin (10mg/kg) | Immunohistochemistry | Inhibition of clinical relapses and epitope spreading | Inhibition of Th1 and Th17 differentiation | |||||||
V) nortriptyline (10mg/kg) | 10-plex LiquiChip (level of cytokines) | Enhancement of Th2 differentiation | ||||||||
5 groups,10 per group | ↓INF-γ, IL-17 (pro-inflammatory) | |||||||||
I) vehicle-control | ↑IL4 (anti-inflammatory) | |||||||||
II) des(1mg/kg) + nor (5mg/kg) | Dose-dependent decrease in inflammatory cytokines | |||||||||
III) des(1mg/kg) + nor (10mg/kg) | and alteration in naïve CD4+ differentiation | |||||||||
IV) des(2mg/kg) + nor (10mg/kg) | ||||||||||
V) des(3mg/kg) + nor (10mg/kg) | ||||||||||
|
|
10mg/kg | Immunization (SC) with incomplete Freud’s adjuvant containing M. Tuberculosis 4mg/ml and 200μg of myelin oligodendrocyte glycoprotein MOG 35-55. | Onset of disease 13+/-1 dpi | Administration of desipramine (dissolved in drinking water) 13 after immunization (acute) or starting from immunization day for 14 consecutive dayschronic) | 4 groups. | 6-8 weeks female C57BL/6 mice | Rotarod |
|
|
|
Acute treatment (DMI for 24h on 13d.p.i) | 18 per group | 18-20g body weight (BW) | Light dark box |
|
|
||||
Chronic treatment (DMI for 14 days) | I) control mice | Open field test | Both treatments (acute/chronic) didn’t improve motor activity or severity of clinical signs | ↓overexpression of CCL5 in the cortex of EAE mice | ||||||
II) EAE mice | Radioactivity measurement | Long lasting restoration of Glutamate exocytosis and cAMP production (↑cAMP) | ||||||||
III) Control +DMI (acute) | cAMP -Quantification assay | |||||||||
control +DMI (chronic) | ELISA kit | |||||||||
IV) EAE mice +DMI (acute) | ||||||||||
EAE mice +DMI (chronic) | ||||||||||
|
|
10mg/kg | Immunization on day 0 and 7 with 300μg MOG | Early onset (day 9) of hyperacute EAE (haEAE) characterized by brain hemorrhage and high mortality rate | Beginning on day 0 mice were either non-handled or injected daily with saline or imipramine | 3 groups | female C57BL mice | Observations in motor deficits, food intake, BW, sucrose drinking and social exploration | Imipramine treated group | |
|
I) non-handled | 4,5-7g body weight (BW) | ↑survival rate | |||||||
II) saline | Attenuated haEAE-associated decrease in BW | |||||||||
III) imipramine | ||||||||||
|
|
25mg/kg | A. Immunization | Onset of clinical signs on 13 day |
|
|
6-8 weeks female C57BL/6 mice | Flow cytometry |
|
|
|
(SC) ( |
Onset of clinical signs 18 dpi |
|
I)vehicle (PBS) n=8 | Approximately 20 g body weight BW | Immunocytochemistry | Disease onset was delayed | ↓mRNA expression of INF-γ, TNF-a, IL-17, CCL2 | ||
with 50μg | Initiation of treatment 5 dpi until day 20 | II) clomipramine (IP) n=8 | 8-10 weeks | Microscopy |
|
|||||
MOG 35-55 |
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Biozzi ABH mice | Live-cell imaging | Suppression of clinical signs | |||||
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Initiation of treatment day 0 until day 15 | I) vehicle (PBS)(n=8) | Histological analyses | Amelioration of weight loss | ||||||
mouse model (progression model) |
|
II) clomipramine (IP) (n=7) | PCR | Attenuation of meningeal inflammation | ||||||
Application of 150 μl emulsion in both sides of hind flanks. Emulsion prepared as follows. |
|
Treatment initiated at |
LC-MS | Reduction of microglial activation (less axonal damage) | ||||||
|
I) vehicle (PBS), n=10 | 1-Treatment initiated at |
||||||||
treatment initiated from clinical |
II) clomipramine (IP), n=10 | No significant difference | ||||||||
treatment from clinical |
|
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I) vehicle (PBS)(n=5) | Reduction of clinical severity of the first relapse (days 14-20) and second relapse at late chronic phase (days 42-50) | |||||||||
II) clomipramine (IP) (n=6) | ||||||||||
treatment initiated from clinical |
treatment initiated from clinical |
|||||||||
I) vehicle (PBS) (n=5) | Reduction of clinical severity | |||||||||
II) clomipramine (n=5) | ||||||||||
|
|
6,20,60mg/kg | Immunization (SC) with 200μg proteolipid protein (PLP) 139-151 | Onset of clinical signs approximately day 10 | Treatment (p.o) initiated at the day of EAE induction | Treatment initiated at EAE induction (oral pretreatment, 14 d treatment) 4 groups (n=8/group) | Age 6-12 weeks | Immunohistochemistry | Treatment initiated at EAE induction (oral pretreatment) (day of adoptive transfer) (14 d): Venlafaxine suppressed EAE in a dose dependent fashion; reduces histopathological manifestation of EAE (20mg/kg) after 3wk treatment. |
|
|
After |
/or after the onset of clinical symptoms. | I) control (PBS) | Female SJL/J mice | ELISA kit | treatment initiated at the beginning of clinical |
|
|||
Control mice received PBS | II) venlafaxine (PO)(6mg) | Cell viability assay | Treatment initiated after manifestation of EAE symptoms: Significant dose dependent amelioration of EAE symptoms after 2wk treatment | ↓mRNA expression of CD3 T-cells, cytotoxic CD8 T-cells, Granzyme B | ||||||
In addition, in another experiment osmotic pumps were implanted (SC) prior to EAE induction and vehicle or 60mg/kg venlafaxine were administered for 14 consecutive days | III) venlafaxine (PO)(20mg) | Real time PCR | Osmotic pump pretreatment: Reduced peak of disease and ameliorated relapses | ↓mRNA expression of pro-inflammatory cytokines | ||||||
IV)venlafaxine (PO)(60mg) | INF-γ, TNF-a, IL-12, chemokines Ccl2 and Ccl5 | |||||||||
treatment initiated at the beginning of clinical |
↑mRNA expression of BDNF | |||||||||
I) control (PBS) | ||||||||||
II)venlafaxine (PO)(6mg) | ||||||||||
III)venlafaxine (PO)(60mg) | ||||||||||
treatment initiated after manifestation of EAE symptoms, 3 groups (n=10/group) | ||||||||||
I)control (PBS) | ||||||||||
II)venlafaxine (PO)(6mg) | ||||||||||
III)venlafaxine (PO)(60mg) | ||||||||||
Osmotic pump pretreatment, 2 groups (n=7/group) | ||||||||||
i)control (PBS) | ||||||||||
iv)venlafaxine(60mg) | ||||||||||
|
(MAO-i) | 15mg/kg | Subcutaneous 50μg MOG 35-55 | Onset of clinical signs approximately 10-14 d (clinical grade 1) | Treatment | 3 groups | 10-12 week-old | Open field assays | ↓clinical score | ↑levels of 5-HT spinal cord (lumbar, thoracic, cervical) |
phenelzine | (IP) initiated from clinical onset (after immunization) and every second day for 14 days(n=14) or daily for 14 consecutive days (n=5) | I) vehicle(saline)+EAE(n=12) | Female C57/BL6 | Rotorod assay | ↑levels of 5-HT, NE, DA within spinal cord, brain, brainstem | |||||
II) PLZ+EAE(n=14) | HPLC | PLZ treatment every second day causes less inhibition of MAO B | ||||||||
III) PLZ+EAE(n=5) | Immunocytochemistry | |||||||||
|
(MAO-i) | 15mg/kg | Subcutaneous 50μg MOG 35-55 | Onset of clinical signs day 15 (clinical grade 3) |
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4 groups | Female C57/BL6 | Open field assays |
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phenelzine | 30mg/kg | 30mg/kg single dose at the “peak” of disease-clinical score ≥3) | I)control-vehicle (CFA) | Rotorod assay | -Delayed onset of clinical signs | ↑levels of 5-HT, NE and GABA in CNS | ||||
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II) control-vehicle (CFA)+ PLZ | HPLC | -reduced impairments |
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15mg/kg 7 days after immunization) | III) EAE | Histological analysis Immunocytochemistry | -Improved locomotor function | Restores 5-HT levels in the ventral horn | ||||||
IV)EAE+ PLZ | -potentiated exploratory behaviors | ↑levels of 5-HT, NE in brainstem, cerebellum, | ||||||||
No difference in GABA | ||||||||||
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15mg/kg | Subcutaneous 50μg MOG 35-55 | Onset of clinical signs day 14-17 dpi | Treatment onset 7 days after immunization. |
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8-12wk old | Rotorod assay | PLZ delayed onset of clinical signs of EAE | PLZ normalized pre-synaptic excitatory synaptic densities in S1; reduced VGLUT1+ density (↓ VGLUT1 reactivity); normalized cortical Iba-1+ reactive microglial cells in S1 (↓excessive cortical Glu release, ↓ cortical microgliosis); normalized neuronal morphologies |
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I) control (CFA) | Female C57/BL6 | FA imaging (FAI) | Chronic PLZ normalized mechanical thresholds in EAE | |||||
II) vehicle(VEH)+EAE | Von Frey hair assay (mechanical sensitivity) | PLZ demonstrated antinociceptive effect | ||||||||
III) PLZ+EAE | Histological analysis | |||||||||
Golgi-Cox staining | ||||||||||
Immunohistochemistry (IHC) | ||||||||||
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amitriptyline | 1,3 and 7mg/kg | Subcutaneous 200μg MOG 35-55 mixed with Quillaja sapon. Three different doses of QuilA (15, 30, 45μg) were assessed | Mechanical allodynia in the bilateral hind paws was fully developed by 28-30 dpi | At 30-55 dpi treatment onset with amitriptyline (IP) | Groups | 4-6wk old | Histologic analysis | Dose-dependent relief of mechanical allodynia in the bilateral hind paws of EAE mice | |
I) Vehicle | Female C57/BL6 | Immunohistochemistry | ||||||||
II) EAE + Amitriptyline (1mg/kg) | Von Frey test Gait analysis (automated Catwalk XT) | |||||||||
III) EAE + Amitriptyline (3mg/kg) | ||||||||||
IV) EAE + Amitriptyline (7mg/kg) | ||||||||||
Sham-mice (n=7)/ EAE-mice (n=32) | ||||||||||
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Imipramine | 10mg/kg | Guinea pig MBP (50μg per rat) | Onset of clinical signs | Chronic imipramine pre-treatment (daily via drinking water) started at the age of 6 weeks | 4 groups (EAE induction 14wk) | 6 week old | Open field test | IMI reversed the increase of deprivation-induced emotionality | ↑plasma levels of IL-4 |
Control (10-11dpi) | EAE was induced 8 weeks after initiation of the imipramine treatment (postnatal week 14) | Control (undisturbed during 28 postnatal days) | Female Lewis rats | Hole-board test | IMI increased exploration of the hole-board | (protective-like effect of IMI may partly be mediated via TH1 to TH2 shift) | ||||
MD (7-8 dpi) | MD (maternal deprivation for 2h daily for 28d) | ELISA | MD-induced aggravation of EAE is reversed by imipramine | No significant changes of corticosterone, INF-γ and IL-10 | ||||||
MD+IMI (8-9 dpi) | MD+ IMI (MD for 2h daily for 28d and imipramine treatment initiating 6wk) | |||||||||
MD+STIM (5-6 dpi) | MD+STIM (MD plus tactile stimulation for 28d) |
Results of
Among MS patients, depression constitutes a highly frequent comorbidity, as studies indicate a 25% prevalence of depression in MS (
Findings encompassed in this review have documented the efficacy of antidepressants in promoting oligodendrocyte maturation and proliferation (
The regulation of T cell proliferation and stimulation by antidepressants reported in some studies of this review (
Studies included in this review also reported the suppression of proinflammatory cytokines induced by antidepressants. Along with several established proinflammatory cytokines such as IL-2, IL-6, IL-12, IL-17, TNFa and IFNγ, antidepressants were also found to reduce serum levels of anti-inflammatory cytokines IL-4 and IL-10, though there has been some evidence supporting some of their immunostimulatory properties (
Although MS is considered a Th1 autoimmune disease in which prevails a CD4+ immune response, CD8+ T cells seem to play a pivotal role in the pathogenesis of major depressive disorder (MDD). Clinical studies revealed that CD8+ T cells are increased in MS patients with depression compared to those without, being traceable in their serum during active phases (
In a clinical scope, antidepressants have proved to be efficient not only in tackling depression comorbid to MS (
Regarding antidepressant use in MS, several adverse events of these drugs could potentially overlap some of the existing deficits that are to be found in MS patients, therefore exacerbating them. To draw an example, SSRIs are known to cause sexual dysfunction, a state that might be already prominent in MS patients, even reaching 85% in female MS patients (
Antidepressants, however, also have the capacity to alleviate numerous MS symptoms. Bupropion can benefit MS patients suffering from chronic fatigue, as this drug has been clinically shown to improve the fatigue severity scale when tested on a patient with MS (
With respect to neuropathic pain, the SNRI duloxetine has been proved to adequately treat this distressing symptom prevalent in more than 25% of MS patients (
Taken together, this evidence suggests that antidepressants have proved to be highly effective not only in treating depression in MS patients (
However, clinical trials on the matter remain scarce and inconclusive due to the relatively confined number of participants and the uniqueness of each trial, rendering their comparison futile (
All things considered, antidepressants have proved effective both in alleviating EAE, an animal model of MS and
ES: manuscript writing, editing, acquisition of data. ID, SS, AA, AM, TA, KS: Analysis and interpretation of data. CS: manuscript editing. GP: manuscript writing, review of the final manuscript. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.